2. Academic Validation
  3. Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel Hs ClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma

Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel Hs ClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma

  • J Med Chem. 2025 Feb 27;68(4):4287-4307. doi: 10.1021/acs.jmedchem.4c02016.
Mingyang Sun 1,  Beijing Chen 1,  Dan Teng 2 3,  Hongshen Zhao 1,  Yilie Liao 1,  Chun Zhang 1 4,  Qi Huang 1,  Huicong Ma 1 4,  Chongyu Wang 1 4,  Xinyi Lin 1,  Peng Yu 1,  Qingning Yuan 2,  Jinghua Yu 5,  Lei Xu 1,  Xiaobei Hu 1,  Fei Ye 6,  Xingxing Diao 5,  Mingyue Zheng 2 3,  Wanchao Yin 1 2,  Yubo Zhou 1 7,  Jia Li 1 2 7,  Mingliang Wang 1 8 4
Affiliations

Affiliations

  • 1 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Tsuihang New District, Zhongshan, Guangdong 528400, China.
  • 2 State Key Laboratory of Drug Research; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 3 Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 4 School of Pharmacy, Zunyi Medical University, Zunyi 563000, China.
  • 5 Center for Drug Metabolism and Pharmacokinetics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 6 College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China.
  • 7 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 8 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
PMID: 39935096 DOI: 10.1021/acs.jmedchem.4c02016
Abstract

The "magic methyl effect" has facilitated the successful development of numerous pharmaceutical compounds. During the development of HsClpP activators, we found that incorporating methyl groups into the bicyclic imipridone scaffolds significantly enhanced the activator activity at the enzymatic level. Further structure-activity relationship studies led to the identification of a highly promising compound, CLPP-2068, which exhibited an EC50 value of 50.4 nM. Cryo-electron microscopy techniques and computational analyses demonstrated that the introduction of methyl groups facilitated the formation of additional CH-π interactions between CLPP-2068 and HsClpP, thereby lowering the energy barriers during the binding process. Furthermore, additional pharmaceutical analyses indicated that CLPP-2068 exhibited favorable pharmacokinetic properties and effectively mitigated the potential hERG toxicity observed in imipridone-based HsClpP activators. Collectively, CLPP-2068, developed using the magic methylation strategy, holds potential as a therapeutic agent for the treatment of diffuse large B-cell lymphoma, thereby expanding the clinical indications for HsClpP activators.

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